Role of histotripsy synergized CD40 signaling in the re-engineering of cold tumors

项目概要 晚期转移性黑色素瘤是最致命的皮肤癌，通常对化疗和化疗具有抵抗力。 放射治疗。对于此类患者来说，免疫检查点抑制剂（ICIs）的出现是一次革命性的改变。 改变，提高肿瘤缓解和生存率，扭转之前缺乏进展的情况。尽管前景光明， 大部分患者，尤其是那些免疫原性较差（“冷”）肿瘤的患者，仅表现出适度的 对 ICI 的反应，甚至反应者经常复发。新的肿瘤再工程技术刻不容缓 需要提高免疫抵抗性冷肿瘤患者的生存率。该项目的目标是 优化基于局部聚焦超声组织解剖 (HT) 和抗组织治疗的创新组合疗法 CD40 激动剂抗体 (aCD40) 封装的聚合物微粒 (CMP) 可重新编程冷黑色素瘤 肿瘤。 HT 无创且快速地在实体癌中产生具有清晰边界的非细胞抗原库， 而aCD40则激活抗原呈递细胞（APC）。我们的小鼠黑色素瘤研究发现 CMP 更有效 与单独使用可溶性 aCD40 相比更有效，并且与 ICI/HT 联合使用可实现完全缓解 未经治疗的肿瘤。基于这个前提，我们将检验中心假设：瘤内给药 具有肿瘤抗原捕获和 HT 持续激活 CD40 双重功能的 CMP 将实现 局部治疗和远端未治疗的黑色素瘤的持久缓解。为了检验我们的假设，目标是 1) 确定 HT 和 CMP 联合方案在免疫原性不同的小鼠肿瘤模型中的功效 和负担，2) 阐明通过 HT 和 CMP 驱动远隔效应的 ICI 耐药逆转机制， 3）将我们的研究结果转化为针对患有自发性恶性黑色素瘤的犬兽医患者的临床试验。 狗黑色素瘤与人类黑色素瘤相似，且转移剧烈，有利于 评估我们的组合疗法的可转化性。将免疫学上的“冷”肿瘤转变为 癌症晚期的免疫原性是一个具有挑战性的目标。该项目的成果将能够快速 通过局部生成可与 CD40 协同作用的大型肿瘤抗原库来激活冷黑色素瘤 信号传导以提高针对局部治疗和远处未治疗肿瘤的疗效。我们的临床研究- 相关模型将告知提高大部分转移性黑色素瘤患者生存率的可行性 与免疫治疗耐药的肿瘤。

Project Summary Advanced-stage metastatic melanoma is the deadliest form of skin cancer, typically resistant to chemo- and radiotherapy. For such patients, the advent of immune checkpoint inhibitors (ICIs) has been a revolutionary change, improving tumor remission and survival rates, reversing prior lack of progress. Although promising, a large proportion of patients, especially those with poorly immunogenic ("cold") tumors, show only modest response to ICIs, and even responders relapse frequently. New tumor-reengineering technologies are urgently needed to improve survival rates in patients with immunoresistant cold tumors. The objective of this project is to optimize an innovative combinatorial therapy based on local focused ultrasound-based histotripsy (HT) and anti- CD40 agonist antibody (aCD40) encapsulated polymeric microparticles (CMPs) to reprogram cold melanoma tumors. HT non-invasively and rapidly generates acellular antigen depots with sharp boundaries in solid cancers, while aCD40 activates antigen-presenting cells (APCs). Our murine melanoma studies found that CMP is more efficacious compared to soluble aCD40 alone, and when combined with ICI/HT achieves complete remission of untreated tumors. Based on this premise, we will test the central hypothesis that intratumorally-administered CMPs that serve the dual functions of tumor antigen capture and sustained CD40 activation with HT will achieve durable remission of locally-treated and remote untreated melanomas. To test our hypothesis, the aims are to 1) Determine efficacy of the HT and CMP combined regimen in murine tumor models varying in immunogenicity and burden, 2) Elucidate ICI resistance reversal mechanisms that drives abscopal effects with HT and CMP, and 3) translate our findings to clinical trials in dog veterinary patients with spontaneous malignant melanoma. Dog melanoma resembles human melanoma, and metastasizes aggressively, and is advantageous for assessing translatability of our combinatorial therapy. Transforming immunologically “cold” tumors to immunogenic ones in advanced stages of cancer is a challenging goal. The project results will enable rapid activation of cold melanomas by locally generating large tumor antigen depots that can synergize with CD40 signaling to improve efficacy against locally treated and distant untreated tumors. Our studies in clinically- relevant models will inform feasibility of improving survival in a large proportion of metastatic melanoma patients with immunotherapy-resistant tumors.